Our extensive evaluation of the airways of patients with refractory chronic rhinosinusitis during the previous funding period of this project resulted in an unexpected finding: in comparison to healthy controls, patients with this condition exhibited nasal mucosal secretory hyporesponsiveness upon localized provocation with histamine. The importance of this phenomenon is accentuated by the concomitant observation that the same patients had excessive mucosal inflammation documented in nasal fluid cytology. In the case of perennial allergic rhinitis, anther chronic inflammatory condition, nasal mucosal inflammation would be associated with mucosal hyperreponsiveness. We now propose that secretory mucosal hyporesponsiveness plays a central pathophysiologic role in patients with refractory rhinosinusitis as it may lead to diminished homeostatic and protective mechanisms against environmental insults such as allergens, irritants and infections. The competitive renewal of this project is, thus, designed to identify the functional elements of the mucosa that contribute to reduced secretory responsiveness and to investigate the pathophysiologic importance of this phenomenon. Using the technique of nasal provocation with stimulants that have specific actions on various mucosal structures, our first aim is to test the hypothesis that the glandular apparatus is mainly responsible for the observed mucosal dysfunction. In our second aim, we will test whether secretory mucosal hyporesponsiveness is a risk factor for worse outcomes after exposure to inducers of allergic, viral and neurogenic inflammation under experimental conditions, as well as a risk factor for poor treatment outcomes. Our third aim will address the hypothesis that secretory mucosal hyporesponsiveness exhibits familial predisposition. This will be tested by comparing the mucosal responsiveness of the siblings of patients with refractory rhinosinusitis to (a) the siblings of our health control group (b) patients with cystic fibrosis, who invariably suffer from refractory rhinosinusitis and have a well characterized genetic defect, and (c) the patients of patients with cystic fibrosis who are obligate carriers of CFTR mutations. This project is an integral part of the overall Program Project Grant the main hypothesis of which remains that epithelial cell/mucosal dysfunction play a central role in the pathogenesis of chronic rhinosinusitis. This project offers a novel hypothesis on the pathophysiologic mechanism of this condition by focusing around an identified secretory mucosal dysfunction. Establishing such a mechanism may lead to new approaches for the treatment of this major, yet poorly managed, health problem.